Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Overexpression of ΔFosB transcription factor(s) increases bone formation and inhibits adipogenesis

Nature Medicine volume 6, pages 985–990 (2000)Cite this article

Abstract

Members of the AP-1 family of transcription factors participate in the regulation of bone cell proliferation and differentiation. We report here a potent AP-1-related regulator of osteoblast function: ΔFosB, a naturally occurring truncated form of FosB that arises from alternative splicing of the fosB transcript and is expressed in osteoblasts. Overexpression of ΔFosB in transgenic mice leads to increased bone formation throughout the skeleton and a continuous post-developmental increase in bone mass, leading to osteosclerosis. In contrast, ΔFosB inhibits adipogenesis both in vivo and in vitro, and downregulates the expression of early markers of adipocyte differentiation. Because osteoblasts and adipocytes are thought to share a common precursor, it is concluded that ΔFosB transcriptionally regulates osteoblastogenesis, possibly at the expense of adipogenesis.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Increased bone density and tissue-specific expression of ΔFosB isoforms in the NSE-ΔFosB mice.
Figure 2: Progressive osteosclerosis in mice overexpressing ΔFosB.
Figure 3: Cell-autonomous increased osteoblastogenesis in primary calvarial cultures of ΔFosB mice.
Figure 4: Decreased adipogenesis in primary calvarial and bone marrow stromal cell cultures of ΔFosB mice.
Figure 5: Molecular in vitro analysis of the role of ΔFosB isoforms during osteoblast differentiation.

Similar content being viewed by others

References

  1. Bellows, C. G., Wang, Y. -H., Heersche, J. N. M. & Aubin, J. E. 1,25-dihydroxyvitamin D3 stimulates adipocyte differentiation in cultures of fetal rat calvaria cells: comparison with the effects of dexamethasone . Endocrinology 134, 2221– 2229 (1994).

    Article  CAS  Google Scholar 

  2. Grigoriadis, A. E., Schellander, K., Wang, Z-Q. & Wagner, E. F. Osteoblasts are target cells for transformation in c-fos transgenic mice. J. Cell Biol. 122, 685– 701 (1993).

    Article  CAS  Google Scholar 

  3. Wang, Z-Q., Liang, J., Schellander, K., Wagner, E. F. & Grigoriadis, A. E. c-fos-induced osteosarcoma formation in transgenic mice: cooperativity with c-jun and the role of endogenous c-fos. Cancer Res. 55, 6244–6251 (1995).

    CAS  PubMed  Google Scholar 

  4. Johnson, R. S., Spiegelman, B. M. & Papaioannou, V. Pleiotropic effects of a null mutation in the c- fosproto-oncogene. Cell 71, 577– 586 (1992).

    Article  CAS  Google Scholar 

  5. Wang, Z. -Q., Ovitt, C., Grigoriadis, A. E., Mohle-Steinlein, U., Ruther, U. & Wagner, E. F. Bone and haematopoietic defects in mice lacking c- fos. Nature 360, 741– 745 (1992).

    Article  CAS  Google Scholar 

  6. Gruda, M. C., van Amsterdam, J., Rizzo, C. A., Durham, S. K., Lira, S. & Bravo, R. Expression of FosB during mouse development: normal development of FosB knockout mice. Oncogene 12, 2177– 2185 (1996).

    CAS  PubMed  Google Scholar 

  7. Chen, J., et al. Transgenic animals with inducible, targeted gene expression in brain. Mol. Pharmacol. 54, 495– 503 (1998).

    Article  CAS  Google Scholar 

  8. Kelz, M. B., et al. Expression of the transcription factor ΔFosB in the brain controls sensitivity to cocaine. Nature 401, 272–276 (1999).

    Article  CAS  Google Scholar 

  9. Soriano, P., Montgomery, C., Geske, R. & Bradley, A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64, 693–702 (1991).

    Article  CAS  Google Scholar 

  10. Hayman, A. R., et al. Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis. Development 122, 3151–3162 ( 1996).

    CAS  PubMed  Google Scholar 

  11. Seifert, M. F. & Marks, S. C. Morphological evidence of reduced bone resorption in the osteosclerotic (oc) mouse . Am. J. Anat. 172, 141– 153 (1985).

    Article  CAS  Google Scholar 

  12. Franzoso, G. L., et al. Requirement for NF-κB in osteoclast and B-cell development . Genes Dev. 11, 3482–3496 (1997).

    Article  CAS  Google Scholar 

  13. Tondravi, M. M., et al. Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Nature 386, 81– 84 (1997).

    Article  CAS  Google Scholar 

  14. Marks, S. C.,Jr. & Lane, P. W. Osteopetrosis, a new recessive skeletal mutation on chromosome 12 of the mouse . J. Hered. 67, 11–18 (1976).

    Article  Google Scholar 

  15. Simonet, W. S., et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density . Cell 89, 309 –319 (1997).

    Article  CAS  Google Scholar 

  16. Ducy, P., et al. Increased bone formation in osteocalcin-deficient mice. Nature 382, 448–452 ( 1996).

    Article  CAS  Google Scholar 

  17. Arneet, R. & Dempster, D. The effect of pH on bone resorption by rat osteoclasts in vitro. Endocrinology 119, 119–124 (1986).

    Article  Google Scholar 

  18. Anderson, R., Woodbury, D. & Jee, W. Humoral and ionic regulation of osteoclast acidity. Calcif. Tissue Int. 39, 252–258 (1986).

    Article  CAS  Google Scholar 

  19. Ducy, P., et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 100, 197–207 (2000).

    Article  CAS  Google Scholar 

  20. Chen, J., Kelz, M. B., Hope, B. T., Nakabeppu, Y. & Nestler, E. J. Chronic Fos-related antigens: stable variants of ΔFosB induced in brain by chronic treatments. J. Neurosci. 17, 4933–4941 (1997).

    Article  CAS  Google Scholar 

  21. Dorheim, M. et al. Osteoblastic gene expression during adipogenesis in hematopoietic supporting murine bone marrow stromal cells. J. Cell Physiol. 154, 317–328 (1993).

    Article  CAS  Google Scholar 

  22. McCabe, L. R., et al. Developmental expression and activities of specific Fos and Jun proteins are functionally related to osteoblast maturation: Role of Fra-2 and Jun D during differentiation. Endocrinology 137 , 4398–4408 (1996).

    Article  CAS  Google Scholar 

  23. Liberati, N., et al. Smads bind directly to the Jun family of AP-1 transcription factors. Proc. Natl. Acad. Sci. USA 96, 4844–4849 (1999).

    Article  CAS  Google Scholar 

  24. Owen, T. A., et al. Coordinate occupancy of AP-1 sites in the vitamin D-responsive and CCAAT box elements by Fos-Jun in the osteocalcin gene: model for phenotype suppression of transcription. Proc. Natl. Acad. Sci. USA 87, 9990–9994 (1990).

    Article  CAS  Google Scholar 

  25. Banerjee, C., et al. TGF-β1 response in the rat osteocalcin gene is mediated by an AP-1 binding site. Endocrinology 137, 1991–2000 (1996).

    Article  CAS  Google Scholar 

  26. Distel, R. J., Ro, H. S., Rosen, B. S., Groves, D. L. & Spiegelman, B. M. Nucleoprotein complexes that regulate gene expression in adipocyte differentiation: direct participation of c-fos. Cell 49, 835–844 ( 1987).

    Article  CAS  Google Scholar 

  27. Stephens, J. M., Butts, M. D. & Pekala, P. H. Regulation of transcription factor mRNA accumulation during 3T3-L1 preadipocyte differentiation by tumor necrosis factor-alpha . J. Mol. Endocrinol. 9, 61– 72 (1992).

    Article  CAS  Google Scholar 

  28. Parfitt, A. M., et al. Bone histomorphometry: Standardization of nomenclature, symbols, and units. Report of the ASBMR histomorphometry nomenclature committee. J. Bone Miner. Res. 2, 595–610 (1987).

    Article  CAS  Google Scholar 

  29. Bellows, C. G., Heersche, J. N. M. & Aubin, J. E. Determination of the capacity for proliferation and differentiation of osteoprogenitor cells in the presence and absence of dexamethasone . Dev. Biol. 140, 132–138 (1990).

    Article  CAS  Google Scholar 

  30. Quarles, L. D., Yohay, D. A., Lever, L. W., Caton, R. & Wenstrup, R. J. Distinct proliferative and differentiated stages of murine MC3T3-E1 cells in culture: an in vitro model of osteoblast development. J. Bone Miner. Res. 7, 683– 692 (1992).

    Article  CAS  Google Scholar 

  31. Cao, Z., Umek, R. M. & McKnight, S. L. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 5, 1538–1552 (1991).

    Article  CAS  Google Scholar 

  32. Aoki, K., et al. They tyrosine phosphatase SHP-1 is a negative regulator of osteoclastogenesis and osteoclast resorbing activity: increased resorption and osteopenia in me v/me v mutant mice. Bone 25, 261–267 (1999).

    Article  CAS  Google Scholar 

  33. Takahashi, N., et al. Osteoclast-like cell formation and its regulation by osteotropic hormones in mouse bone marrow cultures. Endocrinology 122, 1373–1382 (1988).

    Article  CAS  Google Scholar 

  34. Sambrook, J. Fritsch, E. F. & Maniatis, T. Molecular Cloning: A Laboratory Manual 2nd ed. (Cold Spring Harbor Laboratory Press, New York, 1989).

    Google Scholar 

  35. Sabatakos, G., Davies, G. E., Grosse, M., Cryer, A. & Ramji, D. P. Expression of the genes encoding CCAAT-enhancer binding protein isoforms in the mouse mammary gland during lactation and involution. Biochem. J. 334, 205–210 (1998).

    Article  CAS  Google Scholar 

  36. Schreiber, E., Matthias, P., Muller, M. M. & Schaffner, W. Rapid detection of octamer binding proteins with ‘mini-extracts’, prepared from a small number of cells. Nucleic Acids Res. 17, 6419 (1989).

    Article  CAS  Google Scholar 

  37. Baron, R., Vignery, A., Neff, L., Silverglate, A. & Maria, A. S. in Bone histomorphometry: technique and interpretation Vol. 1 (ed Recker, R.R.) 13–35 (CRC Press, Boca Raton, Florida, 1983).

    Google Scholar 

Download references

Acknowledgements

The authors thank Nancy Troiano, Jennifer Juel, Cathy Steffen and Emilia DiDomenico for expert technical assistance. We also thank A. Houghton and W. C. Horne for many helpful discussions and critical reading of the manuscript; G. Karsenty and P. Ducy for providing cDNA probes and the CBFA1 antisera; S. Roman-Roman for supplying rhBMP-2. This work was supported in part by Hoechst Marion Roussel.

Author information

Author notes

  1. G. Sabatakos and N. A. Sims: G. S. and N. A. S. contributed equally to this study

Authors and Affiliations

  1. Departments of Cell Biology and Orthopaedics, Yale University School of Medicine SHM IE-55, 333 Cedar St, New Haven, 06520-8044, Connecticut, USA

    G. Sabatakos, N. A. Sims, K. Aoki, K. Mukhopadhyay, K. Ford & R. Baron

  2. Laboratory of Molecular Psychiatry and Center for Genes and Behavior Yale University School of Medicine, 34 Park St, New Haven, 06520, Connecticut, USA

    J. Chen, M. B. Kelz & E. J. Nestler

  3. Department of Trauma Surgery, Hamburg University School of Medicine, Lottestrasse 59, Hamburg, 22529, Germany

    M. Amling

  4. Hoechst Marion Roussel - France, 102 Route de Noisy, Romainville, 93235, France

    Y. Bouali

Authors
  1. G. Sabatakos
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. N. A. Sims
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. J. Chen
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. K. Aoki
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. M. B. Kelz
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. M. Amling
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Y. Bouali
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. K. Mukhopadhyay
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. K. Ford
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. E. J. Nestler
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. R. Baron
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to R. Baron.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sabatakos, G., Sims, N., Chen, J. et al. Overexpression of ΔFosB transcription factor(s) increases bone formation and inhibits adipogenesis. Nat Med 6, 985–990 (2000). https://doi.org/10.1038/79683

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/79683

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing